Splice‐site variant in the RPS7 5′‐UTR leads to a decrease in the mRNA level and development of Diamond‐Blackfan anemia

Abstract Diamond‐Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by erythroid aplasia. Pathogenic variants in ribosomal protein (RP) genes, GATA1 , TSR2 , and EPO , are considered to be the etiology of DBA. Variants in 5′‐untranslated regions (UTRs) of these genes are poorly studied and can complicate the variant interpretation. We investigated the functional consequences NM_001011.4:c.‐19 + 1G > T variant in the donor splice‐site of the RPS7 5′‐UTR. This variant was found in a family where two sons with DBA were carriers. Father, who also had this variant, developed myelodysplastic syndrome, which caused his death. Search for candidate causal variants and copy number variations in DBA‐associated genes left RPS7 variant as the best candidate. Trio whole exome sequencing analysis revealed no pathogenic variants in other genes. Functional analysis using luciferase expression system revealed that this variant leads to disruption of splicing. Also, a decrease in the levels of mRNA and protein expression was detected. In conclusion, the established consequences of 5′‐UTR splice‐site variant c.‐19 + 1G > T in the RPS7 gene provide evidence that it is likely pathogenic.